Addressing drug resistance is a core challenge in
cancer research, but the degree of heterogeneity in resistance mechanisms in
cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of
circulating tumor cells (CTC) from patients with advanced
cancer to assess mechanisms of resistance to targeted
therapy and reveal opportunities for
precision medicine. Comparison of the genomic landscapes of CTCs and tissue
metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted
therapy. Thus, we assessed by NGS somatic mutations and copy number alterations (CNA) in archived CTCs isolated from patients with metastatic
breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTCs and metastatic tissues. In 76 individual and pooled informative CTCs from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTCs and tissue
metastases. Potentially actionable genomic alterations were identified in tissue but not CTCs, and vice versa. CTC profiling identified diverse intra- and interpatient molecular mechanisms of endocrine
therapy resistance, including loss of heterozygosity in individual CTCs. For example, in one patient, we observed CTCs that were either wild type for ESR1 (n = 5/32), harbored the known activating ESR1 p.Y537S mutation (n = 26/32), or harbored a novel ESR1 p.A569S (n = 1/32). ESR1 p.A569S was modestly activating in vitro, consistent with its presence as a minority circulating subclone. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived fixed CTCs. Tissue and CTC genomic assessment are complementary, and precise combination
therapies will likely be required for effective targeting in advanced
breast cancer patients.Significance: These findings demonstrate the complementary nature of genomic profiling from paired tissue
metastasis and
circulating tumor cells from patients with metastatic
breast cancer.
Cancer Res; 78(4); 1110-22. ©2017 AACR.